Development of Light‐Activated LXR Agonists

Abstract

Activation of the oxysterol-sensing transcription factor liver X receptor (LXR) has been studied as a therapeutic strategy in metabolic diseases and cancer but is compromised by the side effects of LXR agonists. Local LXR activation in cancer treatment may offer an opportunity to overcome this issue suggesting potential uses of photopharmacology. We report the computeraided development of photoswitchable LXR agonists based on the T0901317 scaffold, which is a known LXR agonist. Azolog-ization and structure-guided structure-activity relationship evaluation enabled the design of an LXR agonist, which activated LXR with low micromolar potency in its light-induced (Z)-state and was inactive as (E)-isomer. This tool sensitized human lung cancer cells to chemotherapeutic treatment in a light-dependent manner supporting potential of locally activated LXR agonists as adjuvant cancer treatment.

Light-controlled inhibition of the circadian regulator RORγ

“…[11][12][13] Azobenzene photoswitches have already been applied to probe nuclear hormone receptor types, 14 notably including light-controlled agonists for peroxisome proliferator-activated receptors (PPARs), 15 estrogen receptor, 16 and liver X receptor (LXR). 17 Photopharmaceutical approaches to control circadian rhythms have also emerged, including light-responsive ligands for casein kinase I or CRY1, [18][19][20] highlighting a natural fit of the temporal reversibility of photoswitch chemistry to clock genes. However, despite remarkable potential for both spatially-localised application in inflammation treatment and temporally-specific application in circadian rhythm studies, RORs are unaddressed by photopharmacology.…”

“…MROR6-7 exhibited no significant off-target activity even at 1 µM (up to 200× their RORγ IC50), confirming selectivity even over LXR that binds structurally similar natural and synthetic ligands (Fig 4a). 17 To monitor how in situ E→Z photoswitching of MROR6-7 affects cellular RORγ-regulated gene expression over time, we observed RORγ-dependent mCherry expression in HEK293T cells. MROR6-7 were applied at time zero and kept in the dark (E) or under 365 nm pulses (Z), and mCherry fluorescence was tracked (Fig 4b,c: intensities relative to DMSO [0.1%] controls).…”